The role of NMR in leveraging dynamics and entropy in drug design.

Abhinav Dubey,Mikhail Reibarkh,Haribabu Arthanari,Koh Takeuchi

doi:10.1007/s10858-020-00335-9

Abstract

Summary:Nuclear Magnetic Resonance (NMR) spectroscopy has contributed to structure-based drug development (SBDD) in a unique way compared to the other biophysical methods. The potency of a ligand binding to a protein is dictated by the binding free energy, which is an intricate interplay between entropy and enthalpy. In addition to providing the atomic resolution structural information, NMR can help to identify protein-ligand interactions that potentially contribute to the enthalpic component of the free energy. NMR can also illuminate dynamic aspects of the interaction, which correspond to the entropic term of the free energy. The ability of NMR to access both terms in the free energy equation stems from the suite of experiments developed to shed light on various aspects that contribute to both entropy and enthalpy, deepening our understanding of the biological function of macromolecules and assisting to target them in physiological conditions. Here we provide a brief account of the contribution of NMR to SBDD, highlighting hallmark examples and discussing the challenges that demand further method development. In the era of integrated biology, the unique ability of NMR to directly ascertain structural and dynamical aspects of macromolecule and monitor changes in these properties upon engaging a ligand can be combined with computational and other structural and biophysical methods to provide a more complete picture of the energetics of drug engagement with the target. Such efforts can be used to engineer better drugs.

Highlights

Much like a sculptor transforms a stone into a masterpiece using her artistic tools, a medicinal chemist transforms a molecule in the laboratory setting to a drug in the clinical setting guided by the laws of thermodynamics
Solution state Nuclear Magnetic Resonance (NMR) spectroscopy is used in various stages including fragment-based drug discovery (FBDD), evolution of fragments for high affinity binders, lead optimization and structure-based drug developments (SBDD)[1,2,3]
We have shown that compounds binding to LmrR resulted in a notable increase in the amplitude of ps-ns dynamics at the hydrophobic core of the protein, which is allosteric to the compound-binding interface but connected to a ligand binding helix, C-helix (Fig. 4B)

Summary

Introduction

Much like a sculptor transforms a stone into a masterpiece using her artistic tools, a medicinal chemist transforms a molecule in the laboratory setting to a drug in the clinical setting guided by the laws of thermodynamics. Wand et al have proposed Lipari-Szabo squared generalized order parameter of methyl bearing side chains as a dynamical proxy for overall protein conformational entropy and have empirically calibrated the ‘entropy meter’ on 28 protein-ligand complexes with a broad range of binding affinities[106] In addition to these strategies, the FCT method has been proposed, to estimate the ps-ns dynamics of methyl groups.[53,122] In the FCT experiment, the intensity of the multi quantum methyl proton signal (Imqc) relative to the intensity of the corresponding single quantum methyl proton signal (I1qc) is measured. We need better NMR methods to quantify desolvation of the ligand

Conclusion and future perspectives

Findings

97. Ono S et al Conformation and Permeability